Two-Drug Combo Makes a Difference in FA

A European trial in Friedreich’s ataxia finds that combining two experimental therapies improves heart health and neurological function

Article Highlights:

Combined treatment with the antioxidant idebenone and an iron-removal drug (iron chelator) called deferiprone produced positive effects in 20 individuals with Friedreich's ataxia, in a trial conducted in Barcelona, Spain.

The investigators observed stabilization in neurological function, significant reduction in heart-muscle enlargement and reduced levels of excess iron deposits in the brain.

Further studies are needed to determine the effectiveness of a "cocktail" treatment using antioxidants and iron chelators — and possibly other drugs as well — in FA.

Results from a clinical trial conducted in Spain involving 20 individuals with Friedreich's ataxia (FA) show that a combination therapy using two drugs, idebenone and deferiprone (DFP), demonstrated a "stabilizing effect" in neurological function and reduced abnormal heart-muscle enlargement in participants who received the two-drug combo for a period of 11 months.

The researchers saw indications that average neurologic dysfunction in trial participants slowed. They also observed significant improvement in measurements of cardiac hypertrophy (a thickening of the heart muscle walls) and decreased levels of iron deposits in the brain.

The antioxidant idebenone (brand name Catena/Sovrima) is thought to remove harmful "free radicals" in cells and help produce energy in the cellular power generators called mitochondria. In previous preclinical (laboratory) studies and clinical trials, the drug, similar to coenzyme Q10, has proved safe and well-tolerated at doses up to 2,250 milligrams per day. However, mixed results have been observed with regard to possible benefits in neurologic, cardiac and motor function. (See FA Research: Idebenone Strikes Out Again, and FA Research: Idebenone Not Effective.)

In FA, iron overload in the mitochondria is a major contributor to the disease process. Iron chelators such as DFP are designed to infiltrate cells and their inner structures, bind with excess iron and remove it from the body. Studies of various iron chelators in tissue culture and in people with FA have shown positive results. (See Experiments Suggest Potential Therapeutic Avenue in Friedreich's Ataxia.)

About the new findings

Daniel Velasco-Sanchez at the University of Barcelona (Spain), with colleagues from other Barcelona-based institutions, published their results online Sept. 24, 2010, in the journal Cerebellum.

The investigators studied 20 individuals with FA, ages 8 years to 25 years old, in an open-label trial. In this case, an open-label trial means participants and investigators were aware that everyone was taking idebenone and deferiprone. Fifteen people exhibited signs of mild heart-muscle damage at the beginning of the study, and all were taking 20 milligrams per kilogram per day of idebenone (without deferiprone) before the trial began.

Each trial participant received an oral dose of 20 milligrams per kilogram of body weight per day of DFP, over a period of 11 months.

Neurological evaluations were performed every six months using standardized measurements defined by the International Cooperative Ataxia Rating Scale (ICARS), which scores posture and gait, fine motor function (dexterity), speech and eye-movement problems. Cardiac status was assessed through clinical evaluations, electrocardiograms (which measure electrical activity in the heart), and echocardiograms, which look at heart structure and performance. Magnetic resonance imaging (MRI) was used to measure iron levels in the brain.

Results included the following:

Stabilization in neurological function was observed, as the overall ICARS scores remained stable. Although posture and gait scores worsened, a significant improvement was observed in fine motor function.

Data from echocardiogram testing showed improvement in several variables that measure cardiac hypertrophy, including a significant reduction in thickness of a specific area of heart tissue called the septum.

Analysis revealed significant reduction of iron levels in the brain.

Blood-iron level measurements were significantly decreased in all trial participants after the treatment period.

Side effects were mild and disappeared within two days following treatment. They included nausea, vomiting and stomach pain. In addition, two participants experienced neutropenia (an abnormal decrease in levels of a particular type of white blood cell), but in only one was it significant enough to discontinue treatment. In both individuals, the condition resolved after discontinuation of DFP.

Meaning for people with FA

It's been speculated that an effective treatment for FA may require a "cocktail" made up of more than one drug, such as a combination of an antioxidant and an iron chelator.

Further studies are needed to determine both the potential of and the most effective methods for using combined antioxidant/iron-chelation treatment.

Decreased blood-iron levels could limit the use of long-term therapy with DFP or other iron chelators, and the risk of neutropenia may make such treatments inappropriate for particular individuals with FA.

However, the Barcelona trial does suggest potential for combining drugs aimed at reducing free radical activity and iron overload.